Ginkgo biloba extract (EGb 761 ; EGb) is a standardized extract and one of the most renowned natural compounds specifically to treat neurological conditions. The constituents from the extract are likely to have synergistic effects that have been shown to be protective against oxidative stress injury. However, the cellular mechanisms of protection afforded by Ginkgo biloba are still unclear. We tested the hypothesis that the neuroprotective action of EGb could be due partially to an induction of heme oxygenase 1 (HO1). We and others have reported that modulation of HO activity may well have direct physiological implications in stroke and in Alzheimer disease. Through the use of cultured neurons, we demonstrated that EGb induces HO1 in a dose-dependent manner. Interestingly, our preliminary results indicate that pre-treatment of primary neurons with EGb followed by washing out the cells and then inducing toxicity, either by H202 or glutamate, EGb revealed neuroprotection. This effect is abolished with the heme oxygenase inhibitor (SnPPIX). We are proposing that several of the protective effects of EGb in ischemic conditions could be mediated through beneficial actions of heme degradation and its metabolites. We will first determine the cerebral blood flow, the infarct size, and the neuronal death following cardiac arrest in EGb-treated WT mice and test whether these effects are significantly decreased in the HOI-/- mice. Then, we will determine whether EGb-induced changes in HO1 expression result in changes in iron homeostasis and cell survival in neuronal cultures derived from WT and HOI-/- mice. To further address possible cellular mechanisms of action, primary cultured neurons derived from WT and HOI-/- mice will be used to test their susceptibility to heme toxicity and their role in controlling the iron efflux. These results should indicate if EGb pretreatment can be protective against iron toxicity and cell death and if this protection is abolished in HOI-/- cells. Together, we will test this new hypothesis that some of the beneficial effects attributed to EGb could be attributed to HO1 induction itself and its biological actions. It could provide new pathways to support the theory that EGb could provide brain's resistance in conditions of ischemia and aged-related dementia. [unreadable] [unreadable]